1. Field of the Invention
This invention relates to disubstituted piperidine ether derivatives, pharmaceutical and agricultural compositions containing them and processes for preparing them and methods of using them as antipsychotics in mammals or as fungicides in plants.
2. Prior Art
The most relevant pharmaceutical references are included below. U.S. Pat. No. 4,508,724 (Taylor et al.) describes cardiac agents having the formula: ##STR1## wherein R.sup.1 is hydrogen, loweralkyl or phenylloweralkyl;
R.sup.2 is hydrogen, loweralkyl or acyl; PA1 R.sup.3 is phenyl, 1-naphthyl, 2-naphthyl, 1H-2,3-dihydroinden-4-yl and 1H-2,3-dihydroinden-5 -yl; PA1 m is 2 or 3; and PA1 n is 1 or 2 PA1 Ar is phenyl or phenyl which is monosubstituted or disubstituted by F, Cl, Br, alkyl or alkoxy each of 1-4 carbon atoms, cycloalkoxy of 3-6 carbon atoms, CF.sub.3, CN, alkylthio of 1-4 carbon atoms, SCF.sub.3, OH and/or alkanoyloxy of 1-10 carbon atoms; PA1 R is (1-R.sup.1 -2-pyrrolidyl)-CH.sub.2 -CHR.sup.2, (1-R.sup.1 -2-piperidyl)-CH.sub.2 -CHR.sup.2 - or 1-R.sup.1 -3-Z-4-hexahydroazepinyl; PA1 R.sup.1 is H, alkyl or alkenyl each of up to 4 carbon atoms, cyclopropylmethyl or benzyl; PA1 R.sup.2 is H, alkyl of 1-4 carbon atoms or phenyl; and PA1 Z is alkyl of 1-4 carbon atoms; PA1 R.sup.1 =H, alkyl, CH.sub.2 Ph (when R.sub.2 =H, X=CH.sub.2, Y=2-OEt); PA1 R.sup.2 =H, OH, OCH.sub.3 ; and PA1 Y=H, halogen, alkyl and alkoxy; PA1 R.sup.3 and R.sup.4 are independently optionally substituted phenyl or naphthyl; and PA1 R.sup.5 is (CH.sub.2).sub.n R.sup.6 where n=1 or 2 and R.sup.6 is optionally substituted phenyl or naphthyl. PA1 n is 1 or 2; PA1 R.sup.1 is (lower)alkyl; and PA1 R.sup.2 is hydrogen or methyl. PA1 Ar, Ar' and Ar" independently are phenyl groups optionally substituted with 1 to 5 substituents independently selected from the group consisting of: PA1 Ar and Ar' independently are naphthyl, pyridyl, pyrimidyl, quinolinyl, isoquinolinyl, dimethylisoxazolyl, thiazolyl, benzothiazolyl, fluorobenzothiazolyl, imidazolyl or benzimidazolyl each optionally substituted with 1 to 5 substituents independently selected from the group consisting of: PA1 R.sub.4A is (CH.sub.2).sub.p Ar' (p is 1 to 3) or is selected from the group consisting of alkyl of 4 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 4 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms or alkyl cycloalkyl of 4 to 10 carbon atoms, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of: PA1 R.sub.5 -R.sub.14 independently are H or alkyl of 1 to 4 carbon atoms; PA1 m is 0 to 5; and PA1 n is 0 to 5; provided however that m and n cannot both be 0; provided that except as noted above, all other positions on the piperidine ring are substituted by hydrogen. PA1 R.sub.1 to R.sub.4 independently are H or methyl; and/or PA1 R.sub.4A is (CH.sub.2).sub.p Ar', or alkyl of 4 to 10 carbon atoms, or alkylcycloalkyl of 4 to 8 carbon atoms; and/or PA1 Ar and Ar' independently are naphthyl, pyridyl, quinolinyl, isoquinolinyl, pyrimidyl, or phenyl each optionally substituted with 1 to 3 substituents as listed above; and/or PA1 m+n.ltoreq.3; and/or PA1 p is 1 to 3. PA1 R.sub.1 to R.sub.4 are H; and/or PA1 R.sub.4 A is alkyl of 5 to 6 carbon atoms or (CH.sub.2).sub.p Ar' . Specifically preferred compounds are as follows:
with the proviso that m is never 3 when n is 2. These compounds are also disclosed as having antidepressant activity based on their ability to block the physiological effects of reserpine and related tetrabenzines which act primarily on serotonin.
U.S. Pat. No. 4,225,608 (Uhl et al.) describes antidepressant compounds of the formula: EQU Ar--O--R
wherein:
with the proviso that Ar is p-fluorophenyl only when R is not 2-(1-methyl-2-piperidyl)-ethyl.
The antidepressant activity of the Uhl et al. compounds is related primarily to their reserpineantagonistic action.
Compounds useful as serotonin and noradrenaline uptake inhibitors, having the formula: ##STR2## wherein: X=O or CH.sub.2 ;
are described in Balsamo et al., J. Med. Chem., 30, 222 (1987). These compounds are weak antidepressants when X=CH.sub.2.
EP 0,190,496 describes compounds of the formula: ##STR3## wherein: R.sup.1 and R.sup.2 are H or form a bond;
These compounds are useful for the treatment of disorders related to gastrointestinal motility.
U.S. Pat. No. 3,360,526 discloses agricultural fungicidal compounds of the formula: ##STR4## wherein: X is H or chloro;
The preferred compounds of the reference are those compounds wherein the bond to the ethereal methylene group is located at the 3-position of the pyrrolidine ring and at the 3- or 4-position of the piperidine ring.
EP 004,288 describes 2-substituted piperidines exemplified by the following: ##STR5## where R=H or Me.
In addition, DE 3,614,907 (BASF) describes compounds having fungicidal activity which are structurally similar to those of Formula (I) but which differ in that the bridge between the piperidine ring and Ar is at most one atom and contains only carbon.
None of the cited references nor any known reference suggest the novel compounds of this invention. Some of the compounds described in the prior art, cited above, are representative of antidepressant agents which characteristically exert their effect due to reserpineantagonistic activity.
Unlike the prior art antidepressant compounds, the compounds of the present invention are potent antipsychotic compounds which exert their effect through selective sigma receptor antagonism. Traditionally, antipsychotic agents such as the phenothiazines and butyrophenones have been potent dopamine receptor antagonists which are associated with a high incidence of side effects, particularly Parkinson-like motor effects or extra-pyramidal side effects (EPS) and dyskinesias including tardive dyskinesia at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.
The present invention is related to antipsychotic agents which are selective sigma receptor antagonists rather than the traditional dopamine receptor blockers known in the art, therefore, the compounds of the present invention have low potential for the typical movement disorders associated with dopamine antagonist antipsychotic agents while they maintain the ability to antagonize aggressive behavior and to antagonize hallucinogenic-induced behavior.
In addition the compounds of the present invention are useful for the control of fungal disease in plants